PROJECT SUMMARY: A common feature of most neurological diseases is the premature and aberrant degeneration of neurons. A variety of molecules involved in the promotion or inhibition of neuronal survival have been identified. This proposal focuses on histone deacetylases (HDACs),a family of enzymes that have become the subject of intense investigation recently. Accumulating evidence suggests that in addition to their involvement in a variety of different biological processes, HDACs regulate neuronal survival. The goal of this proposal is to better understand the role of HDACs in the regulation of neuronal survival. The proposal is based on our recent finding that HDAC-relatedprotein (HDRP), an HDAC that is highly expressed in the brain, protects cultured cerebellar and cortical neurons from apoptosis. We also found that c-jun, a protein that is necessary for neurodegeneration in a variety of in vivo and in vitro paradigms is inhibited by HDRP. The inhibition of c-jun is mediated by the direct interaction of HDRPwith c-jun N-terminal kinase (JNK), the enzyme that activates c-jun through its phosphorylation. The overall objective of the proposal is to better undertand the mechanism underlying HDRP-mediated neuroprotection in the hope of developing novel strategies to treat neurodegenerative pathologies. The hypothesis underlying our proposal is that HDRP acts through interaction with JNK, as well as other signaling proteins. Long-term HDRP- deficiency will render the brain vulnerable to damage while overexpression of HDRP in the brain will protect it from neurotoxic insults. One of our specific goals is identify HDRP-interacting proteins in the brain by yeast-two hybrid screening. The role of these interacting proteins in HDRP-mediated neuroprotection will then be studied. Another goal will be to examine how the interaction between HDRP and JNK inhibits c-jun activation using a variety of biochemical and molecular biological approaches. A third goal will be to to examine whether the brains of HDAC-deficient mice possess any abnormalities. Focus will also be placed on characterizing the nature of lesions within the brains of older HDAC-deficient mice. The fourth goal and final goal of our proposal is to examine whether transgenic mice overexpressing HDRP in the brain are more resistant to neuronal loss in an in vivo experimental model of neurodegenerative disease. RELEVANCE: Neurological diseases disrupt the quality of life for patients and cost society billions of dollars annually. While symptomatic treatments are available for many neurological diseases, a cure is not presently available. It is our hope that the results from the studies we propose will shed insight into how HDRP prevents neuronal loss and thus provide novel targets for the development of strategies to treat neurodegenerative pathologies.